Phase 3 ASCEND Study of Pirfenidone in Idiopathic Pulmonary Fibrosis Presented at ATS and Published in NEJM

BRISBANE, Calif., May 18, 2014 /PRNewswire/ -- InterMune, Inc. (NASDAQ: ITMN) today reported that results from the Phase 3 ASCEND study evaluating pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) were presented today at the International Conference of the American Thoracic Society (ATS) in San Diego, and published on-line in the New England Journal of Medicine. Dr. Talmadge King, Professor and Chair, Department of Medicine, University of California, San Francisco and Co-chair of the ASCEND protocol steering committee, presented the ASCEND results.

In ASCEND, pirfenidone significantly reduced decline in lung function as measured by change in percent predicted forced vital capacity (FVC) from Baseline to Week 52 (rank ANCOVA p<0.000001). Additionally, significant treatment effects were demonstrated on both of the key secondary endpoints of change in six-minute walk distance (6MWD) (p=0.0360) and progression-free survival (PFS) (p=0.0001). The secondary endpoint of dyspnea (shortness of breath) was not met. In ASCEND, treatment with pirfenidone was associated with fewer deaths although the study was not powered for and did not reach statistical significance on mortality. A pre-specified analysis of the pooled population from ASCEND and the two Phase 3 CAPACITY studies showed that the risk of all-cause mortality was reduced by 48% at Week 52 in the pirfenidone group compared to the placebo group (Hazard Ratio [HR] 0.52, log rank p=0.0107). In ASCEND, treatment with pirfenidone showed a favorable safety profile and was generally well tolerated.

IPF is a chronic, progressive, and irreversible lung disease characterized by scarring in the lungs, which hinders a person's ability to breathe. The median survival time from diagnosis is two to five years, which makes IPF more rapidly lethal than many malignancies, including breast, ovarian and colorectal cancers.

Dr. King said, "Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side effect profile and fewer deaths."

Dan Welch, Chairman, Chief Executive Officer and President of InterMune, said, "The presentation of the ASCEND results at ATS and publication in the New England Journal of Medicine represents an important milestone in the decade of clinical research we have conducted on pirfenidone. The study results provide strong evidence of pirfenidone's robust treatment effects and augment its already well-established safety and tolerability profile. We currently intend to resubmit the pirfenidone New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the coming weeks."

Primary Endpoint

The magnitude of the treatment effect of pirfenidone was measured by comparing the proportion of patients in the pirfenidone and placebo groups experiencing either a 10% decline in FVC, or death. A 10% decline in FVC in an individual IPF patient is considered clinically meaningful and strongly predictive of a higher risk of mortality. At Week 52, 16.5% of patients in the pirfenidone group experienced an FVC decline of 10% or more or death, compared with 31.8% in the placebo group, representing a 47.9% reduction in the proportion of patients who experienced this meaningful decline in FVC or death. Additionally, at Week 52, the results demonstrated that 22.7% of patients in the pirfenidone group experienced no decline in FVC, compared with 9.7% in the placebo group, representing a 132.5% increase in the proportion of patients who experienced no decline in FVC between Baseline and Week 52.

Treatment Effect on FVC Confirmed in Supportive Analyses

The New England Journal of Medicine publication contains additional supportive analyses of the treatment effect of pirfenidone on FVC change that corroborate the results of the primary analysis. The mean decline from Baseline to Week 52 in FVC volume, a measurement of lung capacity, was 235 mL in the pirfenidone group and 428 mL in the placebo group (absolute difference, 193 mL; relative difference, 45.1%; p<0.0001). The slope of decline in FVC through Week 52 was 122 mL/yr. in the pirfenidone group and 262 mL/yr. in the placebo group (absolute difference, 140 mL/yr.; relative difference, 53.5%; p<0.0001).

Dr. King added, "The compelling statistical result on the primary analysis was corroborated by supportive analyses, all of which resulted in similar conclusions. The results are very robust."

Two Key Secondary Endpoints

Two key secondary endpoints were pre-specified in the ASCEND protocol: change from Baseline to Week 52 in 6MWD and PFS.

6MWD is a measure of exercise tolerance and a 50-meter decrement in 6MWD is considered an independent predictor of mortality in a patient with IPF. In ASCEND, pirfenidone reduced by 27.5% the proportion of patients who experienced a decline in 6MWD of 50 meters or greater or death relative to placebo (p=0.0360).

PFS is a measure of time until death or disease-progression. Disease progression was defined as any of the following: confirmed percent predicted FVC decrement of 10% or greater or confirmed 6MWD decrement of 50 meters or greater. In ASCEND, pirfenidone reduced the risk of death or disease progression by 43% compared to placebo (HR 0.57; 95% confidence interval [CI], 0.43-0.77; p<0.001). Fewer patients in the pirfenidone group compared with placebo experienced a qualifying event for each component of the endpoint: death (3.6% vs. 5.1%), confirmed >/= 10% decline in percent predicted FVC (6.5% vs. 17.7%), and confirmed >/= 50 m decrement in 6MWD (16.5% vs. 19.5%).

Additional Secondary Endpoints

Additional secondary endpoints were pre-specified in the ASCEND protocol: change from Baseline to Week 52 in dyspnea (shortness of breath), all-cause mortality, and treatment-emergent IPF-related mortality.

The secondary endpoint of dyspnea was not achieved. Analysis of UCSD SOBQ scores showed no statistically significant difference between treatment groups at Week 52; 29.1% of patients in the pirfenidone group experienced a >/= 20 point worsening in UCSD SOBQ score or death, compared with 36.1% of patients in the placebo group (absolute difference, 7.0%; relative difference, 19.3%; p=0.1577).

The two mortality analyses were pre-specified for both the ASCEND study and the pooled population of the ASCEND study and the previous Phase 3 CAPACITY studies through 52 weeks. Given the relatively low overall mortality rate in patient populations in one-year IPF studies, ASCEND was not powered to detect a mortality benefit. The pooled analyses increase the statistical power for detection of a mortality effect and provide a more stable estimate of the magnitude of effect.

The pre-specified analysis of the ASCEND study alone showed fewer all-cause and treatment-emergent IPF-related deaths in the pirfenidone group compared to the placebo group. Four percent of patients in the pirfenidone group and 7.2% of patients in the placebo group died during the study (HR 0.55; 95% CI 0.26 to 1.15; p=0.1045). Treatment-emergent IPF-related deaths occurred in 1.1% and 2.5% of patients in the pirfenidone and placebo groups, respectively (HR 0.44; 95% CI 0.11 to 1.72; p=0.2258). The relationship of death to IPF was determined in ASCEND by a blinded adjudication committee.

The pre-specified analyses of mortality in the pooled population (N=1,247) from ASCEND and the two Phase 3 CAPACITY studies showed that the risk of all-cause mortality was reduced by 48% at Week 52 in the pirfenidone group compared to the placebo group (HR 0.52; 95% CI 0.31–0.87; p=0.0107). Additionally, in the pooled population the risk of treatment-emergent IPF-related death in the pirfenidone group compared to placebo was reduced by 68% at Week 52 (HR 0.32; 95% CI 0.14–0.76; p=0.0061).

Safety and Tolerability

In ASCEND, pirfenidone showed a favorable safety profile and was generally well tolerated.

A total of 93.5% and 94.6% of patients completed the study, died or had a lung transplant by study day 365 in the pirfenidone and placebo groups, respectively. The most common adverse events with higher incidence in the pirfenidone group were gastrointestinal (e.g., nausea and dyspepsia) and skin-related (e.g., rash). The gastrointestinal and rash adverse events were generally mild to moderate in severity, manageable, reversible and only infrequently led to treatment discontinuations. A Grade III gastrointestinal adverse event was experienced in 5.4% and 1.4% of patients in the pirfenidone and placebo groups, respectively. A Grade III skin-related adverse event was experienced in 1.8% of patients in the pirfenidone group compared with 0.4% of patients in the placebo group. No patients in either group experienced a Grade IV gastrointestinal or skin-related event.

The percentage of patients discontinuing treatment due to an adverse event was 14.4% in the pirfenidone group and 10.8% in the placebo group. The most common adverse event resulting in treatment discontinuation was worsening of idiopathic pulmonary fibrosis (1.1% of patients in the pirfenidone group vs. 5.4% of patients in the placebo group). The only other adverse events leading to treatment discontinuation in >/= 1% of patients in the pirfenidone group were hepatic enzyme elevation (1.1%), pneumonia (1.1%), rash (1.1%), and decreased weight (1.1%).

Serious adverse events (SAEs) were reported in 19.8% of patients in the pirfenidone group and 24.9% in the placebo group. The most common serious adverse event was worsening of idiopathic pulmonary fibrosis (2.5% of patients in the pirfenidone group vs. 9.7% in the placebo group). There were fewer deaths in the pirfenidone group compared with placebo (2.9% vs. 5.4%).

Elevations of aminotransferase levels at least three times the upper limit of normal occurred in 2.9% of pirfenidone patients (including one case associated with a bilirubin increase) vs. 0.7% of placebo patients. In general, these elevations occurred early, were manageable and reversible, and were similar to those observed in previous pirfenidone studies.

The safety and tolerability profile of pirfenidone was generally consistent with observations from the previous Phase 3 CAPACITY studies, open-label extension studies and post-marketing experience.

"The results from the ASCEND trial reinforce the favorable safety and tolerability profile observed in previous studies of pirfenidone and through real-world experience where it is currently marketed," said Dr. Paul W. Noble, Chair, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, Calif. and Co-chair of the ASCEND protocol steering committee. "As a treating physician, I am pleased that there is such a robust and thorough assessment of the safety and tolerability of pirfenidone, a medicine that may play an important role in managing patients with IPF."

About ASCEND

ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in IPF) is a multinational, randomized, double-blind, placebo-controlled Phase 3 trial designed to evaluate the safety and efficacy of pirfenidone in patients with IPF. Patients (N=555) were randomly assigned 1:1 to receive oral pirfenidone (2403 mg/day) or placebo and were enrolled at 127 centers in the United States, Australia, Brazil, Croatia, Israel, Mexico, New Zealand, Peru and Singapore.

More than 95 percent of eligible patients (those patients who remained on blinded pirfenidone or placebo therapy) who completed the ASCEND study decided to enter the open-label RECAP extension study. RECAP is a study in which all patients receive pirfenidone. RECAP also includes patients rolled over from the company's prior CAPACITY studies, which were completed in late 2008 and enrolled 779 patients in two Phase 3 studies. RECAP provides valuable long-term safety data that further expands the already large safety database for pirfenidone in patients with IPF.

About CAPACITY

Pirfenidone has been studied in multiple Phase 3 clinical trials in patients with IPF, including the two Phase 3 CAPACITY trials sponsored by InterMune.

The CAPACITY program consisted of two concurrent 72-week trials, which enrolled a total of 779 patients. Both trials were multinational, randomized, double-blind, and placebo-controlled. The studies were designed to evaluate the safety and efficacy of pirfenidone in IPF patients with mild to moderate impairment in lung function. The primary endpoint in both studies was the change from Baseline to Week 72 in percent predicted FVC. This endpoint was met with statistical significance in CAPACITY 2 (p=0.001). The secondary endpoints of PFS and categorical change in FVC also achieved statistical significance (p<0.05). Although the primary endpoint was not met in CAPACITY 1 (p=0.501), supportive evidence of a pirfenidone treatment effect was observed on a number of measures, including percent predicted FVC at weeks 24, 36 and 48, and on 6MWD.

Pirfenidone demonstrated a favorable safety profile and was generally well tolerated in both CAPACITY studies. The most frequent side effects reported were photosensitivity rash, gastrointestinal symptoms such as nausea and dyspepsia, and dizziness.

About Pirfenidone

Pirfenidone is an orally active, anti-fibrotic agent that inhibits the synthesis of TGF-beta, a chemical mediator that controls many cell functions including proliferation and differentiation, and plays a key role in fibrosis. Pirfenidone also inhibits the synthesis of TNF-alpha, a cytokine that is known to have an active role in inflammation.

On February 28, 2011, the European Commission (EC) granted marketing authorization for Esbriet® (pirfenidone) for the treatment of adults with mild to moderate IPF. The approval authorized marketing of Esbriet in all 28 EU member states. Esbriet has since been approved for marketing in Norway and Iceland. In 2011, InterMune launched commercial sales of pirfenidone in Germany under the trade name Esbriet, and Esbriet is now also commercially available in various European countries, including key markets such as France, Italy and the UK.

On October 1, 2012, Health Canada approved Esbriet for the treatment of mild to moderate IPF in adult patients. Health Canada designated Esbriet for Priority Review and completed the accelerated review according to target guidelines of 180 days. InterMune launched Esbriet in Canada in January 2013.

Pirfenidone has been marketed as Pirespa® since 2008 in Japan and since 2012 in South Korea by Shionogi & Co. Ltd. Under different trade names, pirfenidone is also approved for the treatment of IPF in China, India, Argentina and Mexico.

Pirfenidone is not approved for marketing in the United States.

About IPF

Idiopathic pulmonary fibrosis (IPF) is an irreversible and ultimately fatal disease characterized by progressive loss of lung function due to fibrosis (scarring) in the lungs, which hinders the ability of lungs to absorb oxygen. IPF inevitably causes shortness of breath, and a deterioration in lung function and exercise tolerance. IPF patients follow different and unpredictable clinical courses and it is not possible to predict if a patient will progress slowly or rapidly, or when the rate of decline may change. Periods of transient clinical stability in IPF, when they occur, inevitably give way to continued disease progression. The median survival time from diagnosis is two to five years, with a five-year survival rate of approximately 20-40 percent, which makes IPF more rapidly lethal than many malignancies, including breast, ovarian and colorectal cancers. IPF typically occurs in patients over the age of 45, and tends to affect slightly more men than women.

About InterMune

InterMune is a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and orphan fibrotic diseases. In pulmonology, the company is focused on therapies for the treatment of idiopathic pulmonary fibrosis (IPF), a progressive, irreversible, unpredictable and ultimately fatal lung disease. Pirfenidone is approved for marketing by InterMune in the EU and Canada under the trade name Esbriet®. Pirfenidone is not approved for sale in the United States. InterMune intends to resubmit the pirfenidone New Drug Application (NDA) to the U.S. FDA in coming weeks to support regulatory registration in the United States. InterMune's research programs are focused on the discovery of targeted, small-molecule therapeutics and biomarkers to treat and monitor serious pulmonary and fibrotic diseases. For additional information about InterMune and its R&D pipeline, please visit www.intermune.com.

Forward-Looking Statements

This news release contains forward-looking statements within the meaning of section 21E of the Securities Exchange Act of 1934, as amended, that reflect InterMune's judgment and involve risks and uncertainties as of the date of this release, including, without limitation, InterMune's expectations regarding the timing for resubmission of its new drug application with the FDA for pirfenidone; the potential to make pirfenidone available as a medicine to IPF patients in the United States and the potential for pirfenidone to play an important role in managing patients with IPF. All forward-looking statements and other information included in this press release are based on information available to InterMune as of the date hereof, and InterMune assumes no obligation to update any such forward-looking statements or information. InterMune's actual results could differ materially from those described in InterMune's forward-looking statements.

Other factors that could cause or contribute to such differences include, but are not limited to, those discussed in detail under the heading "Risk Factors" in InterMune's most recent annual report on Form 10-K filed with the Securities and Exchange Commission (SEC) on February 24, 2014 (the "Form 10-K") and other periodic reports filed with the SEC, including but not limited to the following: (i) the risks related to the uncertain, lengthy and expensive clinical development process for the company's product candidates, including having no unexpected safety, toxicology, clinical or other issues and having no unexpected clinical trial results such as unexpected new clinical data and unexpected additional analysis of existing clinical data; (ii) risks related to the regulatory process for the company's product candidates, including the possibility that the results of the new 52-week Phase 3 clinical trial (ASCEND) having an FVC endpoint may not be satisfactory to the FDA for InterMune to receive regulatory approval for pirfenidone in the United States; (iii) risks related to unexpected regulatory actions or delays, in particular in connection with our planned resubmission of a Class 2 NDA with the FDA seeking approval of pirfenidone or other government regulation generally; (iv) risks related to our ability to successfully launch and commercialize pirfenidone in the United States, if approved by the FDA and (v) InterMune's ability to obtain or maintain patent or other proprietary intellectual property protections. The risks and other factors discussed above should be considered only in connection with the fully discussed risks and other factors discussed in detail in the Form 10-K and InterMune's other periodic reports filed with the SEC, all of which are available via InterMune's web site at www.intermune.com.

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